Pyrimidopyridazine derivatives

ABSTRACT

Compounds of the formula   WHEREIN R1 stands for an aromatic hydrocarbon or a heterocyclic group, which is unsubstituted or substituted, R2 and R3 are the same or different and represent -NH2, a secondary amino group or a tertiary amino group and their pharmaceutically acceptable salts are useful as diuretics. The compounds are produced by reacting a compound of the formula   WHEREIN R1 has the same meaning as above and X is halogen including chlorine, bromine, etc. with an amine corresponding to R2 and R3 in the general formula (I). Compounds of formula (II) are prepared by halogenation of a compound of the general formula (III)   wherein R1 has the same meaning as above.

United States Patent Yurugi et al.

Oct. 9, 1973 PYRIMIDOPYRIDAZINE DERIVATIVES Inventors: Shojiro Yurugi, Kyoto; Shlntaro Kikuchi, Hyogo, both of Japan Assignee: Takeda Chemical Industries, Ltd.,

Osaka, Japan Filed: Sept. 24, 1970 App]. No.: 75,294

Foreign Application Priority Data Sept. 24, 1969 Japan 44/76125 June 24, 1970 Japan 45/54984 US. Cl..... 260/246 B, 260/256.4 F, 260/2565,

424/248 Int. Cl C07d 87/40 Field of Search 260/2564 F, 246 B Primary Examiner-Alex Maze] Assistant Examiner-Jose Tovar Attorney-Wenderoth, Lind and Ponack Compounds of the formula ABSTRACT wherein R, has the same meaning as above and X is halogen including chlorine, bromine, etc. with an amine corresponding to R and R in the general formula [l]. Compounds of formula [ll] are prepared by halogenation of a compound of the general formula [III] wherein R has the same meaning as above.

19 Claims, No Drawings PYRIMIDOPYRIDAZINE DERIVATIVES The present invention relates to novel pyrimidopyridazine derivatives and their pharmaceutically acceptable salts, which have effective diuretic action.

The present invention also relates to intermediates for these derivatives and further relates to a process for the production of these pyrimidopyridazine derivatives and their intermediates.

There have been synthesized many kinds of diuretics, and some of them have been applied to practical use. Typical examples of these are chlorothiazine derivatives, acetazolamide, triamterene, trifrocine, furoceamide, etc.

However, the known diuretics are not entirely satisfactory in view of one or more drawbacks such as promoting the excretion of potassium as well as sodium, causing side effects (e.g., increase of blood glucose level and blood uric acid level) upon long-term administration, and showing rather low diuretic activity and rather high toxicity.

Under these circumstances, the present inventors have made extensive studies for providing effective diuretics accompanied with no such drawbacks as above.

As the result of their studies, the present inventors have succeeded in synthesizing novel pyrimid[4,5-d]- pyridazine derivatives, and have found that these compounds can answer the purpose.

The present invention has been accomplished on the basis of this finding.

Thus, the principal object of the present invention is to provide novel pyrimido[4,5-d]pyridazine derivatives useful as effective and improved diuretics. Another object is to provide intermediates for these novel compounds.

Further object is to provide a method for the production of these novel compounds and their intermediates.

The pyrimido[4,5-d]pyridazine derivatives of the present invention are those represented by the following general formula if [I] taining one hetero atom of the group N, S and O, five.

to six-membered monocyclic ones containing two or more hetero atoms of the group N, S and 0, and nine to IO-membered dicyclic ones containing one or more hetero atoms of the group N, S and 0. Typical examples of the groups are, for example, fury], thienyl, pyridyl, thianaphthenyl, benzofuranyl, quinolyl, oxazolyl, thiazolyl, etc..

Among the heterocyclic groups, the five and sixmembered monocyclic ones containing one hetero atom of the group N, S and O are most preferable.

The aromatic hydrocarbon and heterocyclic groups are unsubstituted or substituted by one or more substituents. The substituents of the above-mentioned aromatic hydrocarbon or heterocyclic group may, for instance, be a lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), halogen (e.g., chlorine, bromine, fluorine, iodine), nitro, a trihalogenomethyl (e.g., trifluoromethyl, trichloromethyl, etc.), an alkoxy such as lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), an aryl (e.g., phenyl, tolyl, naphthyl, etc.), an aralkyl such as phenyl lower alkyl (e.g., benzyl, phenethyl, etc.), an acyl such as monocarboxylic acid acyl (e.g., acetyl, benzoyl, etc.), and acyloxy such as monocarboxylic acid acyloxy (e.g., acetyloxy, benzoyloxy, etc.), carboxyl, hydroxy, amino, monoor dialkylamino, such as monoor dilower alkyl amino, and cyclic amino groups (e.g., pyrrolidino, piperidino, morpholino, piperazino and the like), etc..

The secondary or tertiary amino groups represented by symbols R and R may be same or different, and each of R and R includes, monoarylamino group, a cyclic amino group, a monoalkyl amino group and a dialkyl amino group, the alkyl group may be straight or branched chain or it may be cyclic and preferably has one to six carbon atoms.

The cyclic amino group may contain one or more substituents such as lower alkyls (e.g., methyl, ethyl, etc.) and aralkyls (e.g., benzyl, etc.). The monoor dialkyl amino group also may contain one or more substituents such as hydroxy, aryl (e.g., phenyl, etc.), and lower alkoxy (e.g., methoxy, ethoxy, etc.).

The cyclic amino group is, for example, a five to sixmembered heterocyclic group containing, in addition to the nitrogen atom, 0 or 1 member of the group of O, S or N, and includes, for instance, pyrrolidinyl, piperidyl, morpholino, piperazinyl, N-methyl-piperazinyl, N- benzyl piperazinyl, etc..

The monoor dialkyl amino group includes for instance, methylamino, ethylamino, propylamino, isopropylamino, butylamino, cyclohexylamino, dimethylamino, diethylamino, methylethylamino, benzylamino, 2-ethoxyethylamino, Z-methoxy-ethylamino, N-methyl-2-hydroxyethylamino, N-benzyl-2- hydroxyethylamino, etc..

The monoarylamino contains an aryl group which is monoor dicyclic carboxylic and the group includes, for example, anilino, naphthylamino, etc..

The pharmaceutically acceptable salts of the present compounds include addition salts with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. and with an organic acid such as oxalic acid, maleic acid, malic acid, tartaric acid, methanesulfonlc acid, ethansulfonic acid, etc..

Typical compounds represented by the general formula [I] are exemplified below:

1. 2-Phenyl-5,8-dimorpholinopyrimido[4,5-

d]pyridazine. 2. 2-Phenyl-5,8-dipyrolidinopyrimido[4,5-

d]pyridazine. 2-Phenyl-5,8-dipiperidinopyrimido[4,5-

d]pyridazine. 4. 2-Phenyl-5,8-bis(N-benzylpiperazino)pyrimido- [4,5-d]pyridazino.

5. 2-Phenyl-5,8-bis(ethylamino)pyrimido[4,5!

dlpyridazine 6. 2-Phenyl-5,8-bis(benzylamino)pyrimido[4,5-d]- pyridazine.

7. 2-Phenyl-5,8-bis(isopropylamino)pyrimido[4,5-

dl-pyridazine.

8. 2-Phenyl-5,8-bis(n-propylamino)pyrimido[4,5-d]- pyridazine.

9 2-Phenyl-5 ,8-bis(N-methyl-Z-hydroxyethylamino)-pyrimido[4,5-dlpyridazine l0. 2-Phenyl-5 ,8-bis(N-benzyl-Z-hydroxyethylamino)-pyrimido[4,5-d1pyridazine l l. 2-(4-Chlorophenyl)5,8-dimorpholinopyrimido[4,5-d]-pyridazine.

l2. 2-(4-Chlorophenyl )-5,8-

dipiperidinopyrimido[4,5-d]-pyridazine.

l3. 2-(4-Nitropheny])-5,8-dimorpholinopyrimido[4,5-d]-pyridazine l4. 2-(4-Nitrophenyl)-5 ,S-dipiperidinopyrimido[4,5-

dl-pyridazine.

l 5, 2-( 3-Tolyl)5 ,8-dimorpholinopyrimido[4,5-d

pyridazine l6. 2-(3-Tolyl)-5,8-bis(isopropylamino)- pyrimido] 4,5-d ]-pyridazine l7. 2-( 3-Tolyl )-5 ,8-dipiperazinopyrimido[4,5-d]- pyridazine l8. 2-(4-Chlorophenyl)-5-morpholino-8- isopropylaminopyrimido[4,5-d]pyridazine.

l9. 2-(4-Nitrophenyl)-5-piperidino-8- morpholinopyrimido[4,5-d]pyridazine 20. 2-(4- Chlorophenyl)-5,8-bis(benzylamino)- pyrimido[4,5-d]-pyridazine.

2 l. 2-( 4-Chlorophenyl)-5,S-dianilinopyiimido[4,5-

d]-pyridazine.

22. 2-(B-Naphthyl)5,8-dimorpholinopyrimido[4,5-

dl-pyridazine 23. Z-(B-Naphthyl)-5,8-dipiperidinopyrimido) pyrimido[4,5-d]-pyridazine 24. 2-(B-Naphthyl)-5,8bis(isopropylamino)- pyrimido[4,5-d]-pyridazine 25. 2-(2-Furyl)-5,8-dimorpholinopyrimido[4,5-

d]pyridazine 26. 2-(2-Thienyl)-5,8-dimorpholinopyrimido[4,5-

d]pyridazine 27. 2 -(Z-Pyridyl)-5,8-dimorpholinopyrimido[4,5-

d]pyridazine 28. 2-(2-Thianaphthenyl)-5,8-dimor- 4 38. 2-(2-Thienyl)-5,8-bis(methoxyamino)- pyrimido[4,5-dl-pyridazinc 39. 2-(2-Pyridyl)-5,8-bis(methoxyamino)- pyrimido[4,5-dl-pyridazine 40. 2-Phenyl-5,8-bis( N-methyl-Z-hydroxyethylamino)-pyrimido[4,5d]pyridazine.

The present compounds of the general formula [I] are prepared by the reaction of a compound of the general formula [II] wherein R has the same meaning as above and X is halogen including chlorine, bromine, etc. with an amine corresponding to R and R in the general formula [I].

The compounds ofthe above general formula [ll] are novel ones and can be used as intermediates for various. 7

kinds of compounds among which are the compounds of formula [I]. V

The compounds of the general formula [II] can be prepared by halogenation of a compound of the general formula [III] wherein R has the same meaning as above.

The above-mentioned compounds of the general formula [III] are also novel and can be used as intermediates for various useful compounds including the compounds of the presentinvention.

. The compounds [III] can be prepared by treating a, I

compound of the general formula [IV] H' [IV] wherein R has the same meaning as above with an inorganic acid.

The compounds of the, general formula ['IV] are prepared by reacting a compound of. the general formula NHZ with a compound of the general formula [VI] RO-OHQCb-OOOR" OCOOR to produce a compound of the general formula [VII] and then reacting the compound [VII] with hydrazine wherein R has the same meaning as above and R, R and R' are lower alkyl such as methyl, ethyl, etc..

The reactions involved in the above-mentioned processes are described below;

The following is a more detailed explanation of the respective steps.

The reaction of Step (A) is carried out preferably in a suitable solvent and in the presence of alkali metal alcoholate as a condensation agent.

The solvent may, for instance, be an alcohol (e.g., methyl alcohol, ethyl alcohol, etc.), chloroform, tetrahydrofuran, ethyl acetate, etc. The alkali metal alcoholate may be methylates, ethylates, etc. of sodium,potassium, lithium etc. The reaction of Step (A) is preferably carried out at room temperature or under cooling. The reaction of Step (B) is carried out preferably in a suitable solvent around the boiling point of the solvent used.

The solvent may, for instance, be water, alcohols (e.g. methyl alcohol, ethyl alcohol, etc.), tetrahydrofuran, dioxane or a mixture of two or more thereof.

The amount of hydrazine to be used in the reaction step (B) is preferably about 2 moles or more per mole of the compound [VII].

The reaction of Step (C) is conducted by treating a compound of the general formula [IV]]with an acid.

As the above-mentioned acid, any of the acids which can convert the hydrazinium salt of the general formula 6 [IV] to the corresponding hydroxyderivative of the general formula [III] may be used.

Typical examples of the acids usable are hydrochloric acid, sulfuric acid, acetic acid, etc.

The amount of the acid is usually a slight excess per mole of the compound [IV].

Generally, the reaction of step (C) proceeds easily by contacting a compound of the general formula [IV] with the diluted acid at room temperature or under cooling.

The reaction of the Step (D) is generally conducted by subjecting a compound of the general formula [III] to halogenation in a suitable solvent, and more particularly by heating under reflux a mixture of the compound of the general formula [III] and a halogenating agent.

As the halogenating agent, any of the conventional agents may be used. Typical examples of the halogenating agents are phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, phosphorus trichloride, etc. or a mixture of two or more thereof, which can act also as a reaction solvent.

The above-mentioned solvent may, for instance, be pyridine, dimethysulfoxide, N,N-dimethylformamide, benzene, etc.

The reaction of Step (E) is carried out by reacting a compound of the general formula [II] with an amino corresponding to R and R of the general formula [I].

The reaction is preferably conducted in a suitable solvent or by using a large excess of the abovementioned amine which can act also as a reaction solvent. The solvent may, for instance, be acetone, methyl alcohol, ethyl alcohol, tetrahydrofuran, chloroform, ethylacetate, benzene, etc.

The reaction temperature of the step (E) is generally around the boiling point of the solvent or an amine used in the reaction, but more higher reaction temperature may be used, if desired. When R and R are different in the reaction of Step (E), a compound of the general formula [II] is at first reacted with one of the amines corresponding to R or R and then the product is reacted with the other amino. The product may consist of two isomers in respect with the positions (5 or 8) of the respective groups of R and R The mixture as such can realize the object of the present invention without separation into respective isomers. But, if desired, the separation into respective isomer can be conducted after a conventional method, e.g., extraction with a suitable solvent, followed by a treatment with column-chromatography.

After completion of the reaction, the objective compound of the general formula [I] may be isolated and purified by a conventional method, e.g. extraction with a suitable solvent, followed by evaporation, recrystallization or a treatment with column-chromatography,

etc.

When the objective compound is obtained as a free base, it may be converted to its salt with an acid such as organic acids (e.g., oxalic acid, malic acid, maleic acid, tartaric acid, etc.) and inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc.).

The objective compounds of the general formula [I] have effective diuretic action.

Namely, the present compounds are characterized by the following properties. i 1. The objective compounds of this invention have ef fective and strong diuretic action.

2. The present compounds show extremely low toxicity.

3. The present compounds induce urinary excretion of a large amount of sodium ion, but induce urinary excretion of relatively small amount of potassium ion which is an essential element to human body.

7 Thus, the excretion ratio of urinary Na lK is comparatively high in the present compounds.

4. The present eompoundscan producea marked additional diuretic response in the animal undergoing maximum diuresis with known diuretics. This fact suggests that the mechanism of diuretic action of the present compounds is different from those of known diuretics. Thus, combination of the present compounds with other known diuretics can produce much increased diuretic effect.

5. Even when the present compounds are administered successively for a long time, substantially no side effects (e.g., increase of blood glucose levels and blood uric acid levels is observed.

PHARMACOLOGICAL TEST Taking advantage of the above characteristic properl5 ties, the objection compounds of the present invention 1. Test compounds. 7 can be used as diuretics and are administered for the In the following test, test compounds are referred to purpose per se or in the form of'a pharmaceutically acas follows:

Substituent; Test General formula compound R1 R2 R3 R A 12 Q RIJN\ B N N N C R3 Q -o1 N/ B -NHCH -NH0 CH3 \GH3 H CH;

N b \S/ .I -Q K 2. Material and Method.

Male CRCD/TA rats were deprived of food and water for 20 hours prior to the administration of the test compound.

total K milliequivalent in the excreted urine of the control group (per one rat, average value of 6 rats) The test compound was dissolved or suspended in Significant difference (0.01 P 0.05). physiological saline and administered to the rats in an difference (000' P 0m) amount of 30mg/kg. body weight in terms of the test Significant difference (P 0.0 1. compound by stomach tube in asaline load of 25ml./kg. body weight. v Six rats were used per one test compound. To the For further explanation of the present invention, folcontrol group (six rats), saline of 25ml./kg. was adminlowing Examples are given wherein the word part(s) istered by stomach tube. is based on weight unless otherwise noted, and relation The rats were placed individually in metabolium between part and Volume part corresponds to cages without food or water and a S-hr pooled urine that between gram and milliliter. samples were collected and urine volumes were mea- EXAMPLES sured. And the samples were analyzed for urinary sodium and potassium. Part I [Step (A)] 3. Result. To a mixture of 1.2 parts of benzamidine hydrochloride, 2.4 parts of ethyl ethoxymethyleneoxalacetate TABLE. DlURETlC ACTIVITY IN SALINE-LOADED RATS and 20 volume parts of methyl alcohol is dropwise collection) added sodium methylate dissolved in methyl alcohol Oral .1 h H l f h dose Nu under cooling with ice unti t e p va ue o t e system (mg/kg) UV UkV becomes 8.0 to 8.5, followed by stirring for 4 hours. A 30 6 ***1.93 ***2.15 1.26 ***l.71 After keeping at room temperature overnight, the re- 2 i3 2 112-22 :33; ***,-1", :33: action mixture is subjected to distillation under re- D s ***2.01 **l.68 *l.81 0.97 duced pressure to remove the solvent. B 30 6 ***1.s7 **l.65 *1.s3 1.10 a F 30 6 41 M9 To the residue is added water until an oily substance 3 2g 2 3-3; ,3; is no longer separated and the mixture is subjectedto 1 30 6 ***2I38 ***2:86 1152 "1:71 30 extraction with chloroform to collect the oily subi8 2 H2 .1113? fig 1%; stance. After drying over anhydrous sodium sulfate and Control 6 0 9 7 removing the solvent by distillation, the residue is subjected to distillation under reduced pressure. This procedure gives 2-phenyl-4,5-diethoxycarbonylpyrimidine total volume of urine of the test group o e (per one rat, average value of6 rats) bollmgat 175 to 179 C/O-3mmHg- UV=I I f fih l l Analysls:

O a V0 Lime 0 Ullfle 0 e CO" r0 group (perone rat. average valueoffi rats) Calculated for l6 16 2 4- C, H, N,

9.33 total Na milliequivalent in the excreted urine of the test group (per one rat, average value of6 rats) Found: C, 64.29; H, 5.50; N, 9.30 u,.-.v=

total Na milliequivalent in the excreted urine of After a Simflar manner to the above followmg Com the control group (per one rat, average value of 6 rats) pounds are produced.

Substituent Melting point (M.P.) or General formula R1 R R boiling point (B.P.) C.) RI KN\H COORHI (fHg CzH CZH5 B.P., 180185/0.6 mm. Hg.

COOR" CzHr- CzHs M- 1 -06.

cnn- CzII5 M.P.,124125.

1 C2H5 C2Hs- M.]., 74 H k 1 UZH Y (igIlr, M-l' 0n.

% CzH C2H5 M.P., (decomp.).

/\ C2H5- C2H5 M.P., 94-955.

Part 11 [Steps(B) and (C)]. l. A mixture of 12.8 parts of 2-'phenyl-4,5-diethoxycarbonylpyrimidine, 26 parts of hydrazine monohydrate and 260 volume parts of methanol is heated under reflux for 3 hours. After cooling, the separated crystals 7 parts of 10 weight percent hydrochloric acid. The

whole mixture is stirred at room temperature for 3 hours. The separated crystals are collected by filtration, washedwith water'a'nd' then dried.

This procedure gives 2-phenyl-5,8.-dihydroxypyrimido-[4,5-d] pyridazine as colorless needles.

Melting point: higher than 280C. Analysis:

Calculated for C H N O Found: C, 61.03; H, 3.52; N, 22.20 2. A mixture of 9.2 parts of 2-( 2-thieny1)-4,5-diethoxycarbonylpyrimidine, 9.3 parts of hydrazine hydrate and 190 volume parts of methyl alcohol is heated under reflux for 4 hours. The separated crystals are collected by filtration, washed with methyl alcohol and dried. Then, the crystals are suspended in 200 volume parts of water and to the suspension is added volume parts of 10 weight percent hydrochloric acid.

The whole mixture is stirred at room temperature for 3 hours. The separated crystals are collected by filtration, washed with water, and then dried.

This procedure gives 2-(2-thienyl)-5,8-dihydroxypyrimido[4,5-d]pyridazine as white crystals.

Melting point: higher than 300 C. Analysis:

Calculated for C H N O S-H O: C, 45.46; H, 3.05;

Found C: 45.43; H, 2.99; N, 21.26

After a similar manner to the above, the following compounds are produced.

C, 60.00; H, 3.36; N,

Melting point (M.P.) or boiling point (B.P.)

M .P. higher than 300.

Part. 111 [Step (D)] 1. A mixture of 0.35 part of 2-phenyl-5,S-dihydroxypyrimido[4,5-d]pyridazine, 35' parts ofphosphorus a oxychloride and 1.75 partsflof phosphorus pentachlo- V ride is-heated under reflux for 3 hours.

' After the completion of the reaction, the reaction I 9 mixture is subjected to distillation under reduced pressure to remove the excess of phosphorus oxychloride.

To the residue is added cold water, and the separated crystals are collected by filtration.

The crystals are washed with 5 weight percent aqueous solution of sodium carbonate, and thenjwith 'cold 7 water, and dried.

This procedure gives '2-phenyl-5 ,8-dichloropyrimido- [4,5-d]pyridaaineas pale yellow-brown-powdery Q Melting point: 210 to 213 C (decomposition). i Analysisp Calculated for cgn cl m; c, s2.01';n,i2.is; N, r

EP C15 -Z ..Z-3Q N. 2-9 912 -26 a 2. A mixture of 5.0 parts of 2-(4-ch1orophenyl)-5,8- dihydroxypyrimido[4,5-d]pyridazine, 50 parts of phosphorus oxychloride and 25 parts of phosphorus pentachloride is heated under reflux for 8 hours. After the completion of the reaction,the reaction mixture is subjected to distillation under reduced pressure to remove the excess of phosphorus oxychloride. To the residue is added ice water and the separated crystals are collected by filtration.

This procedure gives 2-(4-chloropheny1)-5,8- dichloropyrimido[4,5-d]pyridazine melting at 240 to 242 C. i 7 Analysis:

Calculated for C H C1 N C, 46.26;v H, 1.62; N,

Found: C, 40.48; H, 2.02; N, 14.59 3. A mixture of 2.4 parts of 2-(2-thienyl)-5,8-dihydroxypyrimido[4,5-d]pyrimidine, 50 parts of phosphorus oxychloride and 10 parts of phosphorus pentachloride is heated under reflux for 8 hours. After the completion g of the reaction, the reaction mixture is subjected to distillation under reduced pressure to remove the excess of phosphorus oxychloride. To the residue is added ice water and the separated crystals are collected by filtration. This procedure gives 2-(2-thienyl)-5,8- dichloropyrimido-[4,5-d]pyridazine melting at 180 C. Analysis:

Calculated for C H Cl- N S: C, 42.42; H, 1.42; N,

Found: C, 42.79; H, 1.39; N, 20.12 4. A mixture of 1.0 part of 2-(2-furyl)-5,8-dihydroxypyrimido[4,5-d]pyridazine, 25 parts .of phosphorus oxychloride and 5 parts of phosphorus pentachloride is heated under reflux for 1 1 hours. After completion of the reaction, the reaction mixture is subjected to distillation under reduced pressure to remove excess of phosphorus oxychloride. To the residue is added ice water under cooling with ice. The separated crystals are collected by filtration, washed with water and, then dried.

This procedure gives 2-(5-chlorofuryl-2)-5,8- dichloropyrimido[4,5-d]pyridazine as pale brown granules melting at 159C.

Analysis: V

Calculated for C l-1 Cl N O C, 39.83; H, 1.00; N,

Found: C, 39.56; H, 1 .21; N, 18.26

After a similar manner to the above, the following compounds are produced.

Part IV [Step(E) l. A mixture of 2.0 parts of 2-phenyl-5,8-dichloropyrimido[4,5-d]pyridazine and 20 parts of morpholine is heated in a water bath at 80 to 85 C for 3 hours. After completion of the reaction, the reaction mixture is subjected to distillation under reduced pressure to remove the excess of morpholine. To the residue is added 30 volume parts of cold water. The separated crystals are collected by filtration and then recrystallized from methyl alcohol. This procedure gives 2- phenyl-S,8-dimorpholinopyrimido[4,5-d]pyridazine as yellow needles. Melting point: higher than 250 C Analysis:

Calculated for C H N O C, 63.47; H, 5.86; N,

Found: C, 63.36; H, 5.77; N, 21.89 10.0 Parts of 2-phenyl-5,8-dimorpholinopyrimido[4,5- d]pyridazine is dissolved in 600 volume parts of hot ethyl alcohol and to the solution is added 200 volume parts of 10 weight percent alcoholic hydrochloric acid. The reaction mixture is kept cold to yield 2-phenyl-5,8- dimorpholino-pyrimido[4,5-dlpyridazine dihydrochloride as yellow needles melting at 192 to 194 C. Analysis:

Calculated for C H N O Cl C, 53.22; H, 5.32; N,

Found: C, 53.54; H, 5.19; N, 18.61 2. 2.8 Parts of 2-phenyl-5,8-dichloropyrimido[4,5-d]- pyridazine is dissolved in 20 volume parts of isopropylamine and the solution is heated at 170 C for 3.5 hours. After cooling, the reaction mixture is subjected to distillation under reduced pressure to remove the excess of isopropylamine. To the residue is added 20 volume parts of cold water under stirring and the separated crystals are collected by filtration. The crystals are recrystallized from methyl alcohol to yield 2- phenyl-S,8-bis(isopropylamino)-pyrirnido[4,5- d]pyridazine as red-orange prisms melting at 265C.

M1. higher than 300.

v Analysis:

The chloroform solution is, at first, washed with 5 w-- eight percent hydrochloric acid until the washings no longer show alkaline, then with 1 weight percent aqueous solution of sodium carbonate and finally with water. The chloroform layer is dried over anhydrous sodium sulfate, and then subjected to distillation under reduced pressure to remove chloroform.

The black oily residue is dissolved in hot methyl alcohol and the solution is decolorized with active carbon. Thus treated solution is kept at room temperature, and the separated crystals are separated and recrystallized from methyl alcohol.

This procedure gives 2-phenyl-5,8-bis( benzylamino)- pyrimido[4,5-d]pyridazine as yellow needles melting at 85 to 87 C.

Analysis:

Calculated for C H N C, 74.62; H, 5.30; N, 20.08

Found: C, 74.33; H, 5.41; N, 20.30 4. A mixture of 20 parts of 2-(4-chlorophenyl)5,8- dichloropyrimido[4,5-d]pyridazine and 20 volume parts of morpholine is heated under reflux in an oil bath for 2 hours. After completion of the reaction, the reaction mixture is subjected to distillation to remove the excess of morpholine. To the residue is added 30 volume parts of cold water and the separated crystals are collected by filtration. The crystals are purified by a column-chromatography using a mixture of acetone and benzene (1:1) as a solvent. The purified crystals are recrystallized from ethyl alcohol to yield 2-(4- chlorophenyl)-5,8-dimorpholinopyrimido[4,5- d]pyridazine as yellow needles melting at 216 to 217 Analysis:

Calculated for c n mo cl; C, 58.18; H, 5.13; N,

20.36 Found: C, 57.88; H, 5.34; N, 20.22 5. A mixture of 1.4 parts of 2-(2-thienyl)-5,8- dichloropyrimido[4,5-d]pyridazine and 14 parts of morpholine is heated under reflux for 4 hours. After completion of the reaction, the reaction mixture is subjected to distillation under reduced pressure to remove the excess of morpholine. To the residue is added 50 volume parts of cold water and the separated crystals are collected by filtration. Then the crystals are dissolved once again in chloroform, and subjected to filtration. The filtrate is subjected to distillation to remove chloroform. The residue is recrystallized from ethyl alcohol to yield 2-(2-thienyl)-5,8- dimorpholinopyrimido[4,5-d]pyridazine as yellow granules melting at 200 to 203 C. Analysis:

Calculated for C H N O S'H O C, 53.72; H, 5.51;

N, 20.89 Found: C, 53.66; H, 5.55; N, 20.95 6. A mixture of 0.4 part of 2-(5-ch1orofuryl-2)-5,8- dichloropyrimido[4,5-d]pyridazine and 4 parts of morpholine is heated under reflux for 4 hours. After completion of the reaction, the reaction mixture is subjected to distillation to remove the excess of morpholine. To the residue is added 20 volume parts of cold water and the separated crystals are collected by filtration. Then, the crystals are subjected to a silica gel column-chromatography using chloroform as a solvent and subjected to distillation to remove the solvent. The residue is recrystallized from ethyl alcohol to give 2-(5- morpholinofuryl-2)-5,8-dimorpholinopyrimido[4,5- d]pyridazine as yellow-red needles melting at 222 C. Analysis:

Calculated for C H N O C, 58.28; H, 6.00; N,

21.62 Found: C, 58.03; H, 5.96; N, 21.57

7. A mixture of 0.5 part of 2-(B-naphthyl)-5,8- dichloropyrimido[4,5-d]pyridazine and 5 parts of morpholine is heated under reflux for 4 hours. After completion of the reaction, the reaction mixture is subjected to distillation to remove the excess of morpho- 5 line. To the residue is added cold water, and separated crystals are collected by filtration. The crystals are recrystallized from ethyl alcohol to yield 2-(B-naphthyl)- Found: c, 6722;11, 5.69; N, 19.51 After a similar way to the above, the following compounds are produced.

Substituent Melting point General formula R1 R2 R3 (M.P.) C.) 1 12 Q g I 141-142(decomp.) N R x f 144(deco111p.)

N N N Q Q 181-182 (decomp.) R; N-CHz- -N N-CH2 Q -NHOH2CH20CH; NHOH2OH2OCH1 -117 Q 4011011201120 0211, NHCH2OH2O C2115 -127 CH W 100-102 a t N/ o Q Q (I311; CH3 CH1 273-21 Q -NHO NHC CH3 CH3 I Melting Substituent point (M.P. General formula R1 R2 R; 0* 0% y/\I 158-159 N N H l -N N N l l E x 1117 I N Melting Substituent point (M.P.) General formula R1 R2 s l CH3 CH3 119-121 CHzCHzOH CH2CH2OH Plus dioxalate.

What is claimed is: 7. A compound as claimed in claim 2, said compound 1. A compound of the formula: being 2-phenyl-5,8-bis(benzylamino)pyrimido[4,5-

d]pyridazine. 8. A compound as claimed in claim 2, said compound /N\/\ being 2-phenyl-5,8-b1s(isopropylammo)pyr1mido[4,5- N d]pyndazme.

N l; 9. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-bis(2-methoxyethylamino)- pyrimido[4,5-d]-pyridazine. n 10. A compound as claimed in claim 2, said com- Where n! pound being 2-phenyl-5,8-bis(2-ethoxyethylamino)- R is naphthyl, phenyl or phenyl monosubstituted by 4 5- i i nitrO, halo 1 to 3 alkyl and 11. A compound as claimed in claim 2, said com- R2 and R are the same or different and a re c to C pound being 2- 1-5 g alkylamino or C, to C dialkylamino which is unhydroxy thylamino)pyrimid0-[4,5-d]pyridazine. substituted of substituted y 1 2 alkoxy of y- 12. A compound as claimed in claim 2, said comdroxy, piperidino, morpholino, pyrrolidino, N- pound b i 2 (3 1 1) 5 8 benzylpiperazino, benzylamino or anilino. di h li imido[4,5-d]pyridazine.

A compound according to claim 18 wherein 13. A compound as claimed in claim 2, said com- 1 is naphthyl, p y or P y monosubstituted y ound being 2-(3-tolyl)-5,8-dipiperidinopyrimido[4,5-

nitro, chloro or methyl, and d] id i 2 and s are the same or different and are 14. A compound as claimed in claim 2, said comp 'Qpy i y yh pound being 2-(3-tolyl)-5,8-bis(isopropylamino)- ethoxyethylamino),N-methyl-N-(2- pyrimido[4, ]Py y y yn anilinoi benzylamino, P p 15. A compound as claimed in claim 2, said comdino, morpholino, pyrr li in n pound being 2-(4-chlorophenyl)-5,8-dimorbenzylpiperazino. 40 pholinopyrimido[4,5-d]-pyrimidine.

3. A compound as claimed in claim 2, said compound 16, A nd as cl i ed i cl im 2, said combeing 2-phenyl-5,8-dimorpholinopyrimido[4,5- pound b i 2-(4-chlQrophenyl)-5,8- d]pyridazine. dipiperidinopyrimido[4,5-d]-pyridazine.

4. A compound as claimed in claim 2, said compound 17, A c mp nd as claimed in claim 2, said combeing -P y py py pound being 2-(4-nitrophenyl)-5,8-dimord]pyridazine. pholinopyrimido[4,5-d]-pyridazine.

S. A compound as claimed in claim 2, said compound 18, A compound as claimed in laim 2, aid combeing -p y p p py pound being 2-(4-nitrophenyl)-5,8- dlpyridazine. dipiperidinopyrimido[4,5-d]-pyridazine.

6. A compound as claimed in claim 2, said compound 19, A u d as l i d in laim 2, said combeing 2-phenyl-5,8-bis(N-benzylpiperazino)- pound b i 2. 1 5 pyrimido[4,5-d]pyridazine. dimorpholinopyrimido[4,5-d]pyridazine. 

2. A compound according to claim 1 wherein R1 is naphthyl, phenyl or phenyl monosubstituted by nitro, chloRo or methyl, and R2 and R3 are the same or different and are isopropylamino, N-(2-methoxyethyl)amino, N-(2-ethoxyethylamino),N-methyl-N-(2-hydroxyethyl)amino, anilino, benzylamino, piperidino, morpholino, pyrrolidino and N-benzylpiperazino.
 3. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-dimorpholinopyrimido(4,5-d)pyridazine.
 4. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-dipyrrolidinopyrimido(4,5-d)pyridazine.
 5. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-dipiperidinopyrimido(4,5-d)pyridazine.
 6. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-bis(N-benzylpiperazino)pyrimido(4,5-d)pyridazine.
 7. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-bis(benzylamino)pyrimido(4,5-d)pyridazine.
 8. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-bis(isopropylamino)pyrimido(4,5-d)pyridazine.
 9. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-bis(2-methoxyethylamino)pyrimido(4,5-d)-pyridazine.
 10. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-bis(2-ethoxyethylamino)pyrimido(4,5-d)-pyridazine.
 11. A compound as claimed in claim 2, said compound being 2-phenyl-5,8-bis(N-methyl-2-hydroxyethylamino)pyrimido-(4,5-d)pyridazine.
 12. A compound as claimed in claim 2, said compound being 2-(3-tolyl)-5,8-dimorpholinopyrimido(4,5-d)pyridazine.
 13. A compound as claimed in claim 2, said compound being 2-(3-tolyl)-5,8-dipiperidinopyrimido(4,5-d)pyridazine.
 14. A compound as claimed in claim 2, said compound being 2-(3-tolyl)-5,8-bis(isopropylamino)pyrimido(4,5-d)pyridazine.
 15. A compound as claimed in claim 2, said compound being 2-(4-chlorophenyl)-5,8-dimorpholinopyrimido(4,5-d)-pyrimidine.
 16. A compound as claimed in claim 2, said compound being 2-(4-chlorophenyl)-5,8-dipiperidinopyrimido(4,5-d)-pyridazine.
 17. A compound as claimed in claim 2, said compound being 2-(4-nitrophenyl)-5,8-dimorpholinopyrimido(4,5-d)-pyridazine.
 18. A compound as claimed in claim 2, said compound being 2-(4-nitrophenyl)-5,8-dipiperidinopyrimido(4,5-d)-pyridazine.
 19. A compound as claimed in claim 2, said compound being 2-( Beta -naphthyl)-5,8-dimorpholinopyrimido(4,5-d)pyridazine. 